tbuckley/cabot-search huggingface dataset:
Abstract 4420: Carbohydrate-CD11b engagement enhances differentiation of tumor-associated myeloid cells in immunotherapy of solid cancers
Authors: Mei Zhang
Journal: Cancer Research (2023)

Abstract Background: Methods to perturb tumor-associated myeloid cell function are being actively pursued to overcome these challenges in immunotherapy and search for a cure. CD11b is a potential therapeutic target to modulate suppressive myeloid derived cells and induce tumor-reactive T-cell responses. However, CD11b can bind to multiple carbohydrate ligands that trigger a variety of myeloid cell functions like adhesion, migration, and even phagocytosis and proliferation. This has created a major challenge to understand the molecular basis by which CD11b converts differences in receptor-ligand binding into subsequent immune signaling responses, and to use this knowledge for therapeutic development. Methods: This study investigated a previously reported carbohydrate ligand, BG34-200, that showed anti-tumor effect through modulating CD11b+ cells. Applying modern approaches of peptide microarray, multi-parameter FACS analysis, cellular/molecular immunological technology, advanced microscopic imaging, and transgenic mouse models of solid cancers, we studied the BG34-200-CD11b carbohydrate-protein engagement and immunological changes it triggered in the context of solid cancers including osteosarcoma, melanoma and pancreatic cancer. Results: Our results show that BG34-200 can mediate direct, specific, multi-site and multivalent binding to integrin CD11b to trigger cellular differentiation in a suppressive tumor-associated myeloid cell subset. In melanoma, osteosarcoma, and pancreatic cancer, we detected this rare myeloid cell subset in blood, which displayed an inflammatory monocyte phenotype and exhibited immunosuppressive behavior. BG34-200-CD11b engagement could induce differentiation of these tumor-associated inflammatory monocytes into dendritic cells by inducing phagocytosis that effectively trigger F-actin cytoskeletal rearrangement and intrinsic ICAM-1 clustering important for antigen presentation and effector T cell stimulation. Conclusions: Our findings improve understanding of molecular basis by which CD11b converts difference in carbohydrate ligands into subsequent immune signaling responses, may lead to development of safe and novel therapies modulating myeloid derived cell function for immunotherapy of solid cancers. Citation Format: Mei Zhang. Carbohydrate-CD11b engagement enhances differentiation of tumor-associated myeloid cells in immunotherapy of solid cancers. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4420.
Abstract 202: Perfused patient-derived tumor organoid models with autologous immune cells for preclinical drug development
Authors: Melissa Millard, Natalie Dance, Teresa M. DesRochers
Journal: Cancer Research (2023)

Abstract The paradigm shift towards inclusion of primary patient samples in preclinical drug development bottlenecks at the tissue procurement step due to an on-going lack of ’research-ready’ tumor samples. Organoid technology was developed as a solution to this hurdle. Their ability to expand in culture makes them a renewable resource similar to cell lines while recapitulating key properties of the primary tissue, including tumor heterogeneity, structural organization and drug responses. As preclinical drug development continues to adopt organoid-based screening technology and immune-oncology agents continue to be advanced, there is high demand for more complex organoid-based models capable of more accurately predicting individual patient drug responses. Due to their development process, the vast majority of organoids do not contain immune cells, resulting in the need to utilize allogeneic immune cells for any immune cell involved interrogation of the models. Maintaining the immune cells for incorporation with the organoid model can overcome this hindrance. Additionally, perfused organoid models offer a complex, ex vivo model with the ability to replicate the mechanical forces imparted by blood flow and interstitial pressure. Compared to 2D and static 3D cultures, perfused 3D culture models show enhanced proliferative and migratory capacities and can be sustained as long-term cultures. In our previous studies, DNA methylation signatures in patient-derived breast microtumors grown in Kiyatec’s 3DKUBE™ perfusion bioreactor matched the primary tissues of derivation. Given the need for more complex biology when assessing immune-oncology agents, the physiological relevance in maintaining gene expression ex vivo, and the capability to sustain long-term viability, the impact of autologous immune cells and perfusion on the success of organotypic culture was investigated across a panel of primary patient tumors. Immune cells were profiled for status and activity and imaging and viability assays were used to evaluate static and perfused 3D organoid models for differences in viability and morphology. PCR was used to examine how mechanically transduced forces alter gene expression and DNA methylation signatures. Drug responses were measured using our KIYA-Predict™ platform, comparing organoid drug responses to primary tissue drug responses. Results of this study provide insight on alternative methods of organotypic culture and evidence for the utilization of more complex tissue modeling in preclinical drug development. Citation Format: Melissa Millard, Natalie Dance, Teresa M. DesRochers. Perfused patient-derived tumor organoid models with autologous immune cells for preclinical drug development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 202.
Abstract 2309: Unlocking the proteome of metastatic prostate cancer circulating tumor cells
Authors: Justin M. Drake, Zoi Sychev, Alec Horrmann, Kaylee J. Smith, Catalina Galeano-Garces, Ali Arafa, Nicholas Heller, Mahdi Ahmadi, Jiarong Hong, Megan Ludwig, Justin Hwang, Emmanuel S. Antonarakis, Jayant Parthasarathy
Journal: Cancer Research (2023)

Abstract In recent years, liquid biopsies have emerged to provide improved insights on the current disease state of a patient, but they generally rely on a small number of protein markers from immunofluorescent staining or cell-free DNA, which provides limited information especially around drug targets. As more targeted and immune therapies enter the market, selecting the optimal drug target could improve patient outcomes drastically. One way to achieve this goal is to generate multi-omic datasets from the cancer cells in circulation, known as circulating tumor cells (CTCs). In this study, Astrin Biosciences’ patented isolation technology was used to enrich CTCs with high purity from the blood of metastatic castration resistant prostate cancer (mCRPC) patients. The enriched CTCs and a patient matched control sample consisting primarily of white blood cells were divided such that RNA and protein could be interrogated from the same patient. Label free unbiased mass spectrometry was used to identify proteins and marks the first time a global proteomic assessment has been performed in CTCs from cancer patients. Initial analysis identified over 1,500 peptides corresponding to greater than 500 proteins with increased epithelial cell markers in the CTC-enriched sample and increased WBC markers in the control sample. Hallmarks of androgen response and detection of the androgen receptor were also identified in the CTC proteome. In addition to the proteome, RNA sequencing will also be performed to generate a multi-omic platform to detect cancer signaling mechanisms and biomarkers. Overall, this study was designed to show the feasibility of obtaining multi-omic data from a liquid biopsy and future studies will provide more insight into the clinical utility of such data. As we analyze more patients, we plan to compare the protein and RNA signatures across mCRPC patients and eventually be able to map patient outcomes and correlate them with drug response with the overall goal to improve treatment selection and patient outcomes. Citation Format: Justin M. Drake, Zoi Sychev, Alec Horrmann, Kaylee J. Smith, Catalina Galeano-Garces, Ali Arafa, Nicholas Heller, Mahdi Ahmadi, Jiarong Hong, Megan Ludwig, Justin Hwang, Emmanuel S. Antonarakis, Jayant Parthasarathy. Unlocking the proteome of metastatic prostate cancer circulating tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2309.
Abstract 3165: ImmuneSig: A deep learning framework to develop gene expression signature of immune checkpoint inhibitor therapy
Authors: Yang Liu, Aashna Jhaveri, Sudhenshna Bodapati, Cheryl Wong, Franziska Michor
Journal: Cancer Research (2023)

Abstract Immune checkpoint inhibitor (ICI) therapy targeting cytotoxic T lymphocyte-associated protein 4 (CTLA-4), programmed death 1 (PD1), and programmed death-ligand 1 (PDL1) induces durable remission in some patients with various cancer types. Given the variable patient outcomes, many studies have been conducted to identify prognostic biomarkers associated with ICI response. However, due to intra- and inter-tumor heterogeneity and the complexity of the immune system, those biomarkers have diverse efficacy for predicting outcomes in clinical trials. Here we propose a deep learning framework with unsupervised self-learning autoencoders that identifies predictive features from patient transcriptomics data. This approach allows us to determine the contribution of each gene to the response classifier and identifies potential gene signatures for predicting immunotherapy response by using the learned weights of trained autoencoders. We applied our framework to 20+ ICI clinical cohorts across different cancer types and compared the prediction performance of our method with other well-known immune response markers evaluated using a suite of machine learning algorithms (random forest, logistic regression, and XGboosting) with cross-validation. We found that in some cohorts, the learned features from autoencoders improve the predictive power of ICI response when evaluated with the area under the operating characteristic curve. Our framework uncovers potential immune gene signatures associated with patient outcomes. Our work will help advance cancer immunology and immuno-oncology research, provide insights into tumor immunity, and lead to the discovery of progressively more immune markers and novel immune targets. Citation Format: Yang Liu, Aashna Jhaveri, Sudhenshna Bodapati, Cheryl Wong, Franziska Michor. ImmuneSig: A deep learning framework to develop gene expression signature of immune checkpoint inhibitor therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3165.
British Thoracic Society guideline for diagnosing and monitoring paediatric sleep-disordered breathing
Authors: Hazel J Evans, Neil A Gibson, Joanna Bennett, Samantha YS Chan, Johanna Gavlak, Katharine Harman, Hasnaa Ismail-Koch, Ruth N Kingshott, Ross Langley, Andrew Morley, Kirstie S Opstad, Kylie Russo, Martin P Samuels, Hui Leng Tan, Daniel Tweedie, Michael Yanney, Andrea Whitney
Journal: Thorax (2023)

Please note that sleep-disordered breathing (SDB) in children without comorbidities is related to snoring and upper airway obstruction and commonly referred to as obstructive sleep apnoea (OSA). ### Diagnosing sleep-disordered breathing in children with suspected sleep-disordered breathing #### Sleep questionnaires, combined sleep questionnaires and 'protocol-driven' clinical assessments, sleep video recordings and sleep audio recordings ##### Children without comorbidities ###### Recommendations ###### Good practice points ##### Children with comorbidities ###### Good practice point #### Pulse oximetry and CRSS ##### Children without comorbidities ###### Recommendation
Polymyxin resistance caused by large-scale genomic inversion due to IS26 intramolecular translocation in Klebsiella pneumoniae
Authors: Haibin Li, Lang Sun, Han Qiao, Zongti Sun, Penghe Wang, Chunyang Xie, Xinxin Hu, Tongying Nie, Xinyi Yang, Guoqing Li, Youwen Zhang, Xiukun Wang, Zhuorong Li, Jiandong Jiang, Congran Li, Xuefu You
Journal: Acta Pharmaceutica Sinica B (2023)

Polymyxin B and polymyxin E (colistin) are presently considered the last line of defense against human infections caused by multidrug-resistant Gram-negative organisms such as carbapenemase-producer Enterobacterales, Acinetobacter baumannii, and Klebsiella pneumoniae. Yet resistance to this last-line drugs is a major public health threat and is rapidly increasing. Polymyxin S2 (S2) is a polymyxin B analogue previously synthesized in our institute with obviously high antibacterial activity and lower toxicity than polymyxin B and colistin. To predict the possible resistant mechanism of S2 for wide clinical application, we experimentally induced bacterial resistant mutants and studied the preliminary resistance mechanisms. Mut-S, a resistant mutant of K. pneumoniae ATCC BAA-2146 (Kpn2146) induced by S2, was analyzed by whole genome sequencing, transcriptomics, mass spectrometry and complementation experiment. Surprisingly, large-scale genomic inversion (LSGI) of approximately 1.1 Mbp in the chromosome caused by IS26 mediated intramolecular transposition was found in Mut-S, which led to mgrB truncation, lipid A modification and hence S2 resistance. The resistance can be complemented by plasmid carrying intact mgrB. The same mechanism was also found in polymyxin B and colistin induced drug-resistant mutants of Kpn2146 (Mut-B and Mut-E, respectively). This is the first report of polymyxin resistance caused by IS26 intramolecular transposition mediated mgrB truncation in chromosome in K. pneumoniae. The findings broaden our scope of knowledge for polymyxin resistance and enriched our understanding of how bacteria can manage to survive in the presence of antibiotics.
Impact of transfer to reference centres and surgical timing on the prognosis of surgically treated patients with infective endocarditis: a prospective multi-centre cohort study
Authors: Pablo Zulet, Carmen Olmos, Javier López, Isidre Vilacosta, Carmen Sáez, Gonzalo Cabezón, Daniel Gómez, Adrián Jerónimo, Javier Pérez-Serrano, J. Alberto San Román
Journal: Clinical Microbiology and Infection (2023)
Safety and efficacy of osimertinib plus bevacizumab as first-line treatment in EGFR-mutated NSCLC with brain metastasis instructed by dynamic monitoring circulating tumor DNA of paired cerebrospinal fluid and plasma.
Authors: Fang Wei, Juan An, Yichun Hua, Kuanyu Wang, Xiaosheng Ding, Lili Zhou, Xixi Zheng, Shibin Sun, Xiaoyan Li
Journal: Journal of Clinical Oncology (2023)

e21182 Background: The management of brain metastases in lung cancer was always a global challenge. Studies have shown that erlotinib combined with bevacizumab could bring progression-free survival benefit for NSCLC. Osimertinib is a third-generation EGFR tyrosine kinase inhibitor with higher CNS penetration. This study was to evaluate the safety and efficacy of osimertinib plus bevacizumab as the first-line treatment for patients with EGFR-positive NSCLC and brain metatases, and reveal the molecular characteristics of intracranial progression by matching plasma and CSF ctDNA. Methods: Patients with EGFR-positive NSCLC and brain metatases were treated with osimertinib (80mg, daily) plus bevacizumab (5mg/kg, every 4 week) as the first-line treatment. CSF and paird plasma ctDNA were collected before osimertinib and at the time of disease stable, intracranial progression and systematic progression, using the next-generation sequencing (NGS) to explore the dynamic changes between them. The primary end point was median CNS progression-free survival (PFS), CNS objective response rate (ORR). The second end point was to explore the molecular mechanism of CNS progression. Results: As the time of data cutoff (Jan 31, 2023), 15 patients were enrolled. 3 patients (20%) progressed in lung, 2 patients (13.3%) progressed in brain, and 1 patient (6.7%) progressed in leptomeningeal and bone, 2 of them still received oral osimertinib (80mg, daily). 9 patients (60%) were in partial or complete reponse and 8 of them continued to receive the original treatment. The median osimertinib exposure time was 16.8 months. The median bevacizumab exposure time was 9.1 months. The median CNS progression-free survival was 15.5 months (6.8 months to not reached). The CNS objective response rate was 93.33%. Six patients received gamma knife radiotherapy before Osimertinib, the median CNS progression-free survival was 14 months (6.8 months to not reached), the CNS objective response rate was 100%. After progression on Osimertinib, paired CSF and plasma ctDNA were analyzed and EGFR C797S, TP53, CDKN2A and etc could be found as resistanct mechanism. Adverse events of grade 3 or worse were observed in 1 patients (6.7%): severe ulcerative colitis, leading to the suspension of osimertinib. 2 patients (13.3%) stopped bevacizumab because of bleeding. Conclusions: This is a mid-term report with immature data. By the end of follow-up, we expected that osimertinib plus bevacizumab could better reduce the risk of intracranial progression and prolong the progression-free survival compared with osimertinib monotherapy. Clinical trial information: KY2021-155-02.
AOST2031: An in-progress COG phase 3 randomized controlled trial comparing open vs thoracoscopic management of pulmonary metastases in patients with osteosarcoma.
Authors: John J Doski
Journal: Journal of Clinical Oncology (2023)

TPS11579 Background: Pulmonary metastasectomy is considered a necessary component of curative therapy in pulmonary metastatic osteosarcoma, however the optimal surgical approach is unknown. Two approaches include open surgery (OSY) including thoracotomy or sternotomy and minimally invasive surgery (MSY) by thoracoscopy. No randomized trial has been completed comparing these approaches in patients with osteosarcoma, however randomized controlled trials in other cancers have not identified superior outcomes in patients undergoing OSY. OSY allows for direct palpation of all lung surfaces and more pulmonary metastatic nodules can be identified during OSY compared to the number predicted by pre-operative imaging. MSY offers the benefit of faster patient recovery, improved quality of life and potential for equivalent surgical control of relevant metastatic disease. Given wide variability in surgical approach and willingness of both surgical oncology and patient advocacy communities to participate in a randomized trial, AOST2031 was developed to address this clinical equipoise. Methods: Eligibility for AOST2031 includes patients &lt; 50 yrs with a histological diagnosis of osteosarcoma and evidence of pulmonary metastases at initial diagnosis or at first recurrence. Patients must have oligometastatic lung metastasis considered resectable by either OSY or MSY, with rapid central review of chest CT images to confirm eligibility. Systemic therapy considered equivalent to methotrexate, cisplatin and doxorubicin is required to be ongoing in newly diagnosed and completed in patients with recurrence. Exclusion criteria include unresectable primary disease, metastatic disease requiring anatomic lung resection, pleural or mediastinal lesions or pleural effusions, progression while receiving initial therapy, extra-pulmonary metastases and prior chest surgery for pulmonary metastases. Patients are randomized 1:1 to either OSY or MSY, with randomization stratified by disease status and risk. The primary outcome is thoracic event free survival, defined as intrathoracic tumor recurrence or death that results from the procedure or a complication related to the procedure. Two-hundred and twenty-five eligible patients are anticipated to answer the primary objective. Secondary objectives include event free, overall survival and . Exploratory objectives include surgical complication rates, patterns of recurrence, use of surgical localization techniques, comparison of CT findings to pathology of resected specimens, and patient reported outcomes. Biologic objectives include the collection of metastatic tissues to facilitate the study of metastatic disease and serial blood samples for future tumor profiling, germline and circulating tumor DNA studies. AOST2031 opened to enrollment at NCTN sites in February 2022. Clinical trial information: NCT05235165 .
Abstract 1240: mSin1 regulates epithelial-mesenchymal transition
Authors: Shile Huang, Yan Luo, Lei Liu, Bing Cheng
Journal: Cancer Research (2023)

Abstract The mammalian target of rapamycin (mTOR) functions as two complexes, mTORC1 and mTORC2. Extensive studies have focused on mTORC1 in the regulation of cell growth, autophagy, and metabolism. However, the role of mTORC2 is poorly understood. mTORC2 has been found to control cell migration, but the underlying mechanism remains to be determined. Here we show that mammalian stress-activated protein kinase interacting protein 1 (mSin1), a unique component of mTORC2, plays an important role in cell migration. Knockout of mSin1 reduced the migration of mouse embryo fibroblasts (MEFs). Similarly, knockdown of mSin1 also inhibited the migration of tumor cells (Rh30 and HeLa). Furthermore, we observed that mSin1 is crucial for the epithelial-mesenchymal transition (EMT). Knockout or knockdown of mSin1 promoted the mesenchymal-epithelial transition (MET), a transition from multipolar or spindle shape to apico-basal polar shape. In addition, depletion of mSin1 increased the cellular protein level of E-cadherin (an MET marker) and decreased the cellular protein levels of N-cadherin and Twist (EMT markers). The results suggest that mSin1 positively regulates cell migration at least partly by promoting induction of EMT. Our findings support that mSin1 is crucial for mTORC2-mediated cell migration. (Supported by the Feist-Weiller Cancer Center, LSU Health Sciences Center, Shreveport, LA, USA) Citation Format: Shile Huang, Yan Luo, Lei Liu, Bing Cheng. mSin1 regulates epithelial-mesenchymal transition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1240.